Highlights of FDA Oncology Approvals in 2023: Bispecific T-cell Engagers, Pediatric Indications, and Inclusive Drug Development

Oncology product approvals in the last year followed trends similar to prior years, with multiple immunotherapies, mole­cularly targeted therapies with diagnostic devices, and the introduction of new viral gene therapy and cell-based treatments (1). This was achieved through strong collaboration between FDA centers including the Oncology Center of Excellence (OCE), the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health. The OCE continued its robust collaboration among international regulators with eight products reviewed under Project Orbis (2).

While underrepresented communities continue to experience unequal access to and participation in drug development, the FDA has remained committed to ensuring that new drugs are safe and effective across a diverse patient population. Recently the FDA published a draft guidance titled Postmarketing Approaches to Obtain Data on Populations Underrepresented in Clinical Trials for Drugs and Biological Products (3). This guidance aims to describe FDA requirements and provide recommendations for obtaining safety and efficacy information on drugs in the post-marketing setting in historically underrepresented patient populations. OCE launched Project ASIATICA (4) this year to catalyze advocacy, research, and policy regarding Asian American, Native Hawaiian, and other Pacific Islander patients with cancer. Initiatives like OCE Project Equity encourage drug developers to proactively address diversity and inclusion in clinical trials (5). Achieving diversity will require examining the policies and procedures used in drug development and iterative refinement based on outcomes (6, 7).

Patients and patient-centric approaches to clinical trials were highlighted in a number of OCE initiatives. OCE published a glossary of patient-friendly clinical terms to improve communication between physicians and patients around oncology clinical trials and informed consent (8). Effective communication is necessary in drug development because, for example, whether a side effect is unacceptable is likely to vary by patient and disease setting. Consistent collection of patient-reported outcomes can better characterize symptomatic side effects and their impacts, and such collection in children is increasingly important to consider as we expand oncology indications to tumors in pediatric patients (9). Finally, OCE launched Project Pragmatica (10) this year to encourage more patient-centric and functionally efficient clinical trials where appropriate. The Pragmatica-Lung Study (NCT05633602) is an early example of a highly pragmatic design that will compare overall survival in two FDA-approved medications, ramucirumab and pembrolizumab, for advanced non–small cell lung cancer (NSCLC).

Highlights of the original New Drug Applications and Bio­logics Licensing Applications approved from November 8, 2022, through October 6, 2023, are presented in Table 1. CDER approved 14 new molecular entities, new biological products, and combination products as of this date, including five bispecific T-cell engager (BiTE) therapies that were granted accelerated approval for the treatment of lymphomas and multiple myeloma. Three bispecific CD20-directed CD3 T-cell engagers were approved, including mosunetuzumab-axgb, which received approval for adult patients with relapsed/refractory (R/R) follicular lymphoma after 2 or more lines of systemic therapy and was the first BiTE approved for the treatment of lymphoma. Glofitamab-gxbm was approved for the treatment of adult patients with R/R diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) and large B-cell lymphoma arising from follicular lymphoma, after 2 or more lines of systemic therapy. Epcoritamab-bysp was approved for adult patients with R/R DLBCL, NOS including DLBCL arising from indolent lymphoma and high-grade B-cell lymphoma (HGBL) after 2 or more lines of systemic therapy. Other bispecific products granted approval included elranatamab-bcmm, a B-cell maturation antigen–directed CD3 T-cell engager, for adult patients with R/R multiple myeloma who have received at least 4 prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Talquetamab-tgvs is a bispecific GPRC5D-directed CD3 T-cell engager indicated for the treatment of adult patients with R/R multiple myeloma who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

With respect to targeted therapies, pirtobrutinib is a new Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of adult patients with R/R mantle cell lymphoma (MCL) after at least 2 lines of systemic therapy, including a BTK inhibitor. New drug approvals in acute myeloid leukemia (AML) included quizartinib, a FLT3 inhibitor, in combination with standard cytarabine and anthracycline induction and cytarabine consolidation and as maintenance therapy following consolidation chemotherapy for the treatment of adult patients with newly diagnosed AML that is FLT3 internal tandem duplication–positive as detected by an FDA-approved test. Along with approval, a risk evaluation and mitigation strategy was implemented because of QT prolongation, torsades de pointes, and cardiac arrest. Olutasidenib, an inhibitor of mutant isocitrate dehydrogenase 1 (IDH1), was approved in adult patients with R/R AML with a susceptible IDH1 mutation as detected by an FDA-approved test.

Original molecularly targeted approvals for solid tumors included adagrasib, a mutant KRAS inhibitor, for the treatment of adult patients with KRAS^G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. Elacestrant, a selective estrogen receptor degrader, was approved for postmenopausal women or adult men with estrogen receptor–positive, human epithelial growth factor receptor-2 (HER2)–negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Although the clinical trial included patients regardless of estrogen receptor mutational status, the FDA determined that the clinical benefit was predominately in the patients with ESR1-mutated tumors. Mirvetuximab soravtansine-gynx, an antibody–drug conjugate (ADC) comprised of a folate receptor-alpha (FRα)–directed antibody and microtubule inhibitor, was approved for adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic treatment regimens.

Two rare disease therapies were approved. Retifanlimab-dlwr, a programmed death receptor-1 (PD-1) blocking antibody, received accelerated approval for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). A combination product of melphalan, an alkylating agent, was approved under orphan drug designation with a first-in-class drug/hepatic delivery system for liver-directed treatment of adult patients with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.

CBER approved an intravascular adenoviral vector-based gene therapy, nadofaragene firadenovec-vncg, for adult patients with high-risk Bacillus Calmette-Guérin unresponsive non–muscle-invasive bladder cancer with carcinoma in situ with or without papillary tumors. The cell-based therapy, omidubicel, was approved for adult and pediatric patients (12 years and older) with hematologic malignancies who are planned for umbilical cord blood transplantation following myeloablative conditioning to reduce the time to neutrophil recovery and the incidence of infection.

Several drugs received approval for new formulations to expand their indication to pediatric patients who may have difficulty with adult-friendly formulations (e.g., tablets), including dabrafenib and trametinib as tablets for oral suspension. Bosutinib was formulated in capsules, allowing the drug to be mixed with applesauce or yogurt. Another approval allowed a change from dosing of asparaginase erwinia chrysanthemi (recombinant) every 48 hours to a more convenient Monday, Wednesday, and Friday schedule.

Supplemental efficacy approvals in oncology expanded indications to broader populations such as pediatric patients. Dabrafenib with trametinib was approved for the treatment of pediatric patients 1 year of age and older with low-grade glioma. Combination therapy was also approved for pediatric patients 1 year and older with unresectable or metastatic solid tumors with BRAF^V600E mutation who have progressed following prior treatment and have no satisfactory alternatives. Bosutinib was approved for pediatric patients 1 year and older with chronic phase Philadelphia chromosome–positive chronic myelogenous leukemia, newly diagnosed or resistant or intolerant to prior therapy. Data submitted in response to a pediatric written request led to the approval of brentuximab vedotin for pediatric patients 2 years and older with previously untreated high-risk classic Hodgkin lymphoma, in combination with chemotherapy. Supplemental approvals for immunotherapies included nivolumab alone and in combination with ipilimumab for adult and pediatric patients 12 years and older with unresectable or metastatic melanoma. Nivolumab was approved for the adjuvant treatment of adult and pediatric patients 12 years and older with melanoma who have undergone complete resection. Atezolizumab received orphan drug designation for alveolar soft-part sarcoma in adult and pediatric patients 2 years and older with unresectable or metastatic disease. For adult cancers, both abemaciclib and palbociclib, individually with endocrine therapy, received expanded approvals to include adult patients (i.e., premenopausal women and men) for the treatment of hormone receptor (HR)–positive, HER2-negative in both adjuvant and advanced or metastatic breast cancer. The restriction to patients with tumors expressing Ki-67 ≥20% was removed for adjuvant abemaciclib.

The OCE continued to monitor existing drugs in the post-marketing setting to ensure their benefits outweighed their risks. Several efficacy supplements were completed that resulted in narrowed indications for poly (ADP-ribose) polymerase (PARP) inhibitors including niraparib, talazoparib, and olaparib to patients with BRCA mutations, for maintenance treatment of recurrent ovarian cancer, as the FDA identified potentially detrimental overall survival for the PARP class of drugs in patients without BRCA mutations. In addition, oversight of pending confirmatory trials continued under the OCE's Project Confirm initiative (11). Seven drugs were converted from accelerated approval to regular approval following fulfillment of their post-marketing requirements, including avelumab for patients with metastatic MCC, pralsetinib for adult patients with metastatic RET fusion-positive NSCLC, blinatumomab for patients with CD19-positive precursor acute lymphoblastic leukemia, cemiplimab-rwlc for patients with metastatic basal cell carcinoma, polatuzumab vedotin-piiq in combination with bendamustine and a rituximab product for R/R DLBCL, pembrolizumab for metastatic, microsatellite instability–high (MSI-H) or mismatch-repair-deficient (dMMR) solid tumors and colorectal cancer, and dostarlimab-gxly for dMMR recurrent or advanced endometrial cancer. Four accelerated approval indications were withdrawn, including pralsetinib for adult and pediatric patients with advanced RET-mutant medullary thyroid cancer, ibrutinib for adult patients with marginal zone lymphoma, ibrutinib for adult patients with MCL, belantamab mafodotin-blmf for adult patients with R/R multiple myeloma, and atezolizumab for patients with locally advanced or metastatic urothelial carcinoma.

Several immunotherapy agents in combination with chemo­therapy received supplemental approval for locally advanced and metastatic NSCLC. Approvals included cemiplimab for the first-line treatment of NSCLC with no EGFR, ALK, or ROS1 aberrations, durvalumab with tremelimumab-actl for adult patients with no sensitizing EGFR mutations or ALK genomic tumor aberrations, and tremelimumab with durvalumab for adult patients with metastatic NSCLC with no sensitizing EGFR or ALK genomic aberrations. Pembrolizumab monotherapy was approved for adjuvant treatment of patients with stage IB, II, or IIIA NSCLC following complete resection. Dostarlimab with carboplatin and paclitaxel followed by dostarlimab as a single agent was approved for primary advanced or recurrent endometrial cancer that is dMMR as determined by an FDA-approved test or MSI-H. Polatuzumab vedotin-piiq was approved in combination with rituximab and chemotherapy for adult patients with previously untreated DLBCL, NOS, and HGBL and an International Prognostic Index score of 2 or greater.

The FDA approved several targeted therapies, including zanubrutinib, a BTK inhibitor, for adult patients with chronic lymphocytic leukemia/small cell lymphoma. Tipiracil and trifluridine were approved for use in combination with bevacizumab for adult patients with metastatic colorectal cancer previously treated with chemotherapy, an anti-VEGF biological therapy, and an anti-EGFR therapy. Tucatinib was approved in combination with trastuzumab for adult patients with RAS-wild-type, HER2-positive, unresectable, or metastatic colorectal cancer that has progressed following chemotherapy. For locally advanced or metastatic HR-positive, HER2-negative breast cancer, sacituzumab govitecan-hziy was approved for adults who have received three systemic therapies in the metastatic setting. Enfortumab vedotin-ejfv received approval in combination with pembrolizumab for adult patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. Two PARP inhibitors were approved in biomarker-defined populations. Talazoparib was approved in combination with enzalutamide for homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer (mCRPC). Olaparib was approved in combination with abiraterone and prednisone (or prednisolone) for adult patients with deleterious or suspected deleterious (BRCAm) mCRPC. A fixed-dose combination of niraparib with abiraterone and prednisone was approved for adult patients in combination with abiraterone and prednisone for BRCAm mCRPC.

OCE's Project Renewal continued its work to update older oncology drug prescribing information to ensure that it is scientifically up-to-date and clinically meaningful (12). Two product labels were updated last year, including capecitabine, an antimetabolite indicated for multiple cancers, with new and revised indications. Other revisions were made to dosing, including an optional lower starting dose for breast cancer. Temozolomide is an alkylating agent with new/revised approvals for adults with newly diagnosed and refractory anaplastic astrocytoma. Additionally, the dosage regimen, risks, and patient counseling sections were updated. Work continues to update other drugs in collaboration with external oncology experts, fellows, FDA staff, and the referenced licensed drug holders.

Working across FDA product centers and engaging with the outside oncology community, the FDA OCE continues to drive the development and regulation of medical products for patients with cancer. The approvals, policy, and research efforts of the last year reflect a commitment to advancing the development of safe and effective therapies for all patients with cancer.

No disclosures were reported.